Project Summary Unprecedented progress in our ability to elucidate genetic changes in multiple myeloma (MM) has led to long lists of candidate driver genes that are urgently awaiting biological validation ? not only to enhance our understanding of the natural history and genetic underpinnings of MM, but also to prioritize molecular targets for new myeloma therapies and preventions. We will employ a newly developed, comprehensive preclinical research strategy to evaluate in-depth a candidate myeloma driver that appears to be very promising from a translational point of view: the forkhead box M1 transcription factor, FOXM1. The long-term goal of this research is to improve the outcome of myeloma and related plasma cell neoplasms. The main objective is to elucidate the mechanism by which putative myeloma drivers, such as FOXM1, promote tumor development, acquisition of drug resistance and relapse with refractory disease. The central hypothesis is that myeloma drivers increase the tumorigenicity, clonogenicity and therapy resistance of malignant plasma cells and, therefore, provide a rational molecular target for new approaches to myeloma treatment and prevention. Three Specific Research Aims have been designed to test this hypothesis and achieve the objective of this application. The studies in Aim 1 will evaluate the role of FOXM1 in myeloma biology and genetics. The experimental strategy includes the evaluation of drug responses in myeloma cells containing elevated levels of FOXM1 and clinical studies on FOXM1-dependent tumor progression. The anticipated outcome includes evidence that FOXM1 is a worthy target of new treatment approaches that include repurposed FDA-approved drugs. The studies in Aim 2 will determine whether FOXM1 drives neoplastic plasma cell development in laboratory mice. The experimental strategy relies on the determination of tumor incidence and onset in mice reconstituted with transgenic B-lymphocytes that harbor elevated levels of FOXM1. Also included are FOXM1- targeted treatment studies using tumor -bearing mice. The anticipated outcome includes support for the contention that FOXM1 promotes myeloma development and determines, in part, the drug response of myeloma cells. The studies in Aim 3 will assess the genetic network of FOXM1 in myeloma. The experimental strategy involves the determination of FOXM1-dependent gene expression changes in myeloma cells and the mapping of FOXM1 binding sites in the myeloma genome. The anticipated outcome includes increased network-based understanding of the mechanism by which FOXM1 promotes neoplastic plasma cell development. Supported by strong preliminary results that provide a sound rationale for this application, the proposed research is poised to facilitate novel targeted approaches to the therapy and prevention of multiple myeloma.